JPH04275231A - Method of using super oxide dismutase for prevention and treatment of organic rejection for critical patient having multiple injury as a result of accident - Google Patents

Abstract

PURPOSE: To provide a method for using superoxide dismutase for prevention and/or treatment of organic failures in patients at risk with polytrauma caused by accident. CONSTITUTION: Superoxide dismutase is used for prevention and/or treatment of organic failures, especially multiorgan failures in patients at risk with polytrauma caused by accident. In this time, the administration is carried out at a daily dose of 1-15g for at least 2 day after first wound, especially by intravenous injection and natural or recombinant human copper/zinc superoxide dismutase is preferably used as the dismutase.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to the use of superoxide dismutase in the prevention and/or treatment of organ rejection in at-risk patients with multiple trauma as a result of an accident.

0002

BACKGROUND OF THE INVENTION Multiorgan rejection is the most frequent cause of death in patients with multiple trauma as a result of an accident who survive the first 24 hours after a primary surgical procedure. The etiological mechanisms that lead to this life-threatening complication have so far remained unclear. Therefore, targeted treatment or prevention of this complication has not been possible until now.

In the case of sepsis and subsequent organ rejection,
Clinical symptoms are due almost exclusively to microbial invasion and endotoxin release. Furthermore, it has been described and reported that endotoxins cause activation of a number of damaged mediators, especially the complementary system resulting in the formation of oxygen radicals. However, despite significant advances in basic research on septic shock, it remains unclear how important oxygen radicals, along with other mediators, are. However, various experimental studies have shown the beneficial effects of superoxide dismutase administration in sepsis models with respect to disease course and mortality.

On the other hand, superoxide dismutase is not effective in animal experimental trauma models in either rats or primates (Circ. Shock 31,
Abstract No. 8; 1990). Therefore, whether oxygen radicals, along with other mediators, play a significant role in accident-induced polytrauma remains open and rather unlikely.

[0005]

SUMMARY OF THE INVENTION Surprisingly, the present inventors have discovered that after administering high doses of superoxide dismutase to patients with multiple injuries as a result of an accident, the risk of life-threatening complications of post-trauma can be reduced. It has been found that significant beneficial effects on development are observed, including single and multiple organ rejection. In this case, there are no side effects that can be caused by high doses of superoxide dismutase over several days. This advantageous effect arises from the fact that the result of multiple injuries from such multiple traumas can be interpreted as Reperfusion syndrome (known as a source of oxygen radicals) which occurs repeatedly.

The subject of the present invention is therefore the use of superoxide dismutase for the prevention and/or treatment of organ rejection in at-risk patients with multiple trauma as a result of an accident.

[0007]

SUMMARY OF THE INVENTION Superoxide dismutases are naturally occurring metal proteins that generally disproportionate superoxide radicals to less toxic hydrogen peroxide. Enzymes generally contain one or two metal cations, such as iron, manganese, copper, zinc, cadmium, cobalt or mercury. The human enzyme and superoxide dismutase, which is mostly derived from infants,
Contains a combination of copper and zinc ions. human copper
/zinc- superoxide dismutase each 15
It consists of two identical subunits with three amino acid residues and contains one copper and zinc atom per subunit. The dimeric enzyme has a molecular weight of 32.000D. However, a tetrameric copper/zinc superoxide dismutase of eukaryotic origin with a molecular weight of 130.000 D has also been described. Manganese superoxide dismutase of eukaryotic origin is a tetramer with a molecular weight of 80,000 D, while the microbial origin of the iron- and manganese forms is a dimer with a molecular weight of about 40,000 Daltons.

Known methods for obtaining superoxide dismutase are, for example, starting from red blood cells, liver or other tissues (eg German Patent Nos. 1,924,230 and 2).
259405 and German Patent Application No. 22
59404 or European Patent No. 19477). For example, human superoxide is acetylated at the N-terminus, whereas superoxide dismutases obtained from other natural products do not have this feature.

Alternatively, superoxide dismutase can also be obtained from cultured and transformed cells. For example, this is international patent application WO87/01387
It is stated in the specification of the issue.

The production of superoxide dismutase from transformed microorganisms or yeast is described, for example, in German Patent Application No. 3639725, European Patent No. 1
80964 and European Patent Application No. 172
No. 577 and No. 284105. Finally, mention may also be made of methods for producing superoxide dismutase using yeast recombinant DNA engineering, which are described, for example, in EP 138,111 and EP 213,628. In the method of European Patent Application No. 138111, human superoxide dismutase is
Obtained in terminally acetylated form.

The copper-/zinc-superoxide dismutase obtained in yeast transformed according to the description of European Patent Application No. 0138111, which is also used in the clinical trials described below, has a minimum specific activity of 3. ．．
000 units/mg (J. Biol. Chem
．． 244, pp. 6049-6055; 1969). Its amino acid sequence is identical to the natural human origin of copper-/zinc-superoxide dismutase, which was e.g.
e-Seyler) Z. Physiol. Ch
em. 364, pp. 675-690 (1983).

Medicaments or pharmaceutical preparations or forms of use (for indications other than those mentioned here) containing superoxide dismutase as active substance are described, for example, in US Pat. No. 3,637,640 and in European patent application No. 172,577. No. 295826 and No. 34262
It is already known from specification no. All of these drugs
Also contemplated is the use according to the invention of superoxide dismutase for other indications limited herein.

When superoxide dismutase is used in accordance with the present invention for the prevention and/or treatment of organ rejection in at-risk patients with multiple trauma as a result of an accident, superoxide dismutase is generally administered to the patient by intravenous infusion. administration in a form that ensures constant and sufficiently high plasma concentrations for several days. This procedure must be started as soon as possible after the accident or primary surgical procedure. The dosage should then be about 1 g/about 15 g per day. Therefore 30.000 per liter of plasma
A plasma concentration of ˜1.000.000 units superoxide dismutase is obtained. A suitable form for infusion therapy is a sterile, pyrogen-free, optionally carbohydrate-stabilized superoxide dismutase preparation obtained in particular by lyophilization.

[0014] The duration of infusion therapy depends on the particular patient condition and the patient's general condition. This is at the discretion of the treating physician, but generally administration must be carried out for at least two days and may be carried out for ten days.

[0015]

[Example] In a patient with multiple injuries as a result of an accident,
Surprisingly, the clinical trials described below demonstrate the significant improvement that superoxide dismutase infusion can produce in the development of life-threatening complications following trauma, including the avoidance of organ rejection. Can: Randomize 24 patients into parallel groups in a double-blind, placebo-controlled manner: ── 2
Severity Score (ISS) greater than or equal to 7
” (Greenspan et al., J.
．． Trauma 25 (1985) 60-64)
Multi-trauma patients (age 18 years and older) with a difficulty level of - treatment initiated no more than 48 hours after the accident (i.e., initial trauma).

Patients suffer many fractures and soft tissue injuries from traffic or driving accidents. Patients with significant cranio-brain trauma will be excluded from the study.

[0017] Infusion therapy is started as soon as possible after the primary surgical procedure. Administer 3 g of recombinant superoxide dismutase per day for 5 days. The entire observation time is 1
4 days, while increasing its continuous clinical and biochemical parameters. This increase in parameters is similar to that of Goris et al. (Arch. Surg. 1).
20, pp. 1109-1115; 1985), the necessity for analysis using the "Multi-Organ Failure-Score" (MOF-Score) described in the literature is highly compatible. Furthermore, it increases biochemical parameters, such as elastase-plasma concentrations, which are important for further elucidation of the underlying disease mechanisms of post-traumatic organ rejection. German Physician Periodical 8
7, pp. 952-956 (1990), the plasma concentration of granulocyte-elastase is
Correlates with the incidence of post-traumatic complications in polytrauma patients. According to this, the elastase concentration was 85 on the fifth day after the accident.
μg/l is the discrimination limit, above which there is a high incidence of complications including organ rejection.

In the clinical trial conducted, the elastase concentration on the 5th day after the accident (ie on the 6th day of the study) was 57.9±5.7 μg/g for the group of patients treated with superoxide dismutase. It is l. Discrimination point 85μ
The number of patients with elastase concentrations above and below g/l is summarized in the following table ("SOD" = superoxide dismutase).

Elastase concentration on day 1
<85μg
/l >85μg/l SOD
1
11 Placebo
2
10
Elastase concentration on day 6
<85μ
g/l >85μg/l S
OD 11
1* Placebo
5
7 * Similar differences in patients with elastase concentration 86 μg/l in the patient group treated with superoxide dismutase, 104 ± 16 mg/ml acute phase protein compared to 160 ± 19 mg/ml in the placebo group. (C-
Reactive proteins) are also found.

[0020] The general clinical effects regarding the difficulty of post-traumatic complications were evaluated using the aforementioned MOF-
Indicate using a score. The evaluation of the MOF-score showed that organ function was significantly improved in patients treated with superoxide dismutase compared to the placebo group, as evidenced by the accompanying figures showing improved organ function with lower score values. It clearly shows the function of the organ. The MOF-score evaluation therefore shows the same morphology as the laboratory data. Thus, in patients with multiple accidental traumas, a significant beneficial effect was observed under treatment with superoxide dismutase regarding the occurrence of post-traumatic complications;
I can admit it.

[0021]

According to the present invention, organ rejection can be prevented by using superoxide dismutase in patients with multiple traumas due to accidents.

[Brief explanation of the drawing]

FIG. 1 shows the effect of superoxide dismutase on organ function.

Claims (7)

[Claims] 1. A method of using superoxide dismutase for the prevention and/or treatment of organ rejection in at-risk patients with multiple trauma as a result of an accident. 2. Use of superoxide dismutase according to claim 1 in the treatment of patients with multiple traumas as a result of an accident, at a dosage of 1 to 15 g, preferably 2 to 8 g per patient per day. 3. A method of using superoxide dismutase according to claim 1 or 2 for a period of 2 to 10 days after the initial trauma. 4. A method of using superoxide dismutase according to any one of claims 1 to 3, wherein the superoxide dismutase is administered by intravenous infusion. 5. A method of using superoxide dismutase according to any one of claims 1 to 4, wherein a natural or recombinant human copper/zinc superoxide dismutase is used. 6. A method for preventing and/or treating organ rejection in at-risk patients with multiple accidental traumas, characterized in that superoxide dismutase is injected parenterally as a therapeutic agent. 7. The method of claim 6, wherein the superoxide dismutase is administered in a dosage sufficient to obtain a plasma concentration of 30.000 to 1.000.000 units of superoxide dismutase per liter of plasma.